Mahendra Nath Srivastava

Cassane Diterpenes from Caesalpinia bonduc.

Three cassane diterpene hemiketals, caesalpinolide-C, caesalpinolide-D, caesalpinolide-E and one cassane furanoditerpene were isolated from Caesalpinia bonduc. The molecular structures were elucidated using NMR spectroscopy in combination with IR, UV and mass spectral data and relative stereochemistries were determined through ROESY correlation. The isolated compounds were tested for their antiproliferative activity against MCF-7 (breast adenocarcinoma), DU145 (prostate carcinoma), C33A (Cervical carcinoma) and Vero (African green monkey kidney fibroblast) cells.

A withanolide coagulin-L inhibits adipogenesis modulating Wnt/β-catenin pathway and cell cycle in mitotic clonal expansion

Obesity is a result of adipocyte hypertrophy followed by hyperplasia. It is a risk factor for several metabolic disorders such as dyslipidemia, type-2 diabetes, hypertension, and cardiovascular diseases. Coagulanolides, particularly coagulin-L isolated from W. coagulan has earlier been reported for anti-hyperglycemic activity. In this study, we investigated the effect of coagulin-L on in vitro models of adipocyte differentiation including 3T3-L1 pre-adipocyte, mouse stromal mesenchymal C3H10T1/2 cells and bone marrow derived human mesenchymal stem cells (hMSCs). Our results showed that, coagulin-L reduces the expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), the major transcription factors orchestrating adipocyte differentiation. Detailed analysis further proved that early exposure of coagulin-L is sufficient to cause significant inhibition during adipogenesis. Coagulin-L inhibited mitotic clonal expansion (MCE) by delayed entry in G1 to S phase transition and S-phase arrest. This MCE blockade was caused apparently by decreased phosphorylation of C/EBPβ, modulation in expression of cell cycle regulatory proteins, and upregulation of Wnt/β-catenin pathway, the early stage regulatory proteins of adipogenic induction. Taken together all evidences, a known anti-hyperglycemic agent coagulin-L has shown potential to inhibit adipogenesis significantly, which can be therapeutically exploited for treatment of obesity and metabolic syndrome.

Spermicidal Activity of Bivittoside D from Bohadschia vitiensis

BACKGROUND A recent revelation about increased susceptibility to HIV by use of nonoxynol-9 (N-9) has called for identification of novel molecules with potent sperm-attenuating activity and lower side-effect profile, as suitable alternatives. The present study was designed to investigate spermicidal activity in Bohadschia vitiensis whole-body extracts followed by isolation and characterization of bioactive molecule. METHODS Bohadschia vitiensis (Semper) was collected from the Southern Andaman coast of India. Freshly collected marine animals were extracted with methanol. A portion of the crude extract was fractionated into four fractions by macerating with hexane, chloroform, and n-butanol successively. All fractions were evaluated for spermicidal activity. Because maximum activity was localized in the n-butanol soluble fraction, it was chromatographed over a silica gel column, and elution with chloroform-methanol-water (35:10:2, v/v) yielded the major compound bivittoside D (400 mg). Bivittoside D [molecular weight (MW) 1426] is a lanostane triterpenoid with six monosaccharide units. The structure of the compound was established on the basis of physicochemical data, acid hydrolysis of saponin, identification of sugar units and aglycon, melting point, and by comparison with data reported in the literature. RESULTS The aqueous methanol extract of the Bohadschia vitiensis caused 100% mortality of human sperm at 0.01% concentration in vitro, whereas N-9 (reference control) exhibited an equivalent activity at 0.05%. On further fractionation, activity was localized in n-butanol soluble fraction from which the major compound purified was a lanostane triterpenoid called bivittoside D. Bivittoside D was found to be a more potent spermicide (approximately 2.3 times) than N-9 and killed 100% human sperm at the concentration of 350 muM in approximately 20 sec in vitro. Supravital staining and hypoosmotic swelling test revealed sperm membrane permeabilization by bivittoside D as the major mode of spermicidal action. However, bivittoside D was much safer than N-9 towards normal vaginal flora (Lactobacillus) in vitro, although it affected the viability of HeLa cells like other surfactants. CONCLUSION Bivittoside D from B. vitiensis can adequately replace N-9 in vaginal contraceptives to make them more vaginally safe and ecofriendly.

Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents

This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.

Antimalarial activity in Xylocarpus granatum (Koen).

The antimalarial activity of Xylocarpus granatum fruits and their active constituents gedunin and xyloccensin-I were investigated using an in vitro model in this study. The chloroform fraction of X. granatum fruits was found to show promising antimalarial activity using an in vitro model of Plasmodium falciparum. On purification of the active fraction, four pure compounds were isolated and characterised, namely gedunin, photogedunin, xyloccensin-I and palmitic acid. Out of these only gedunin and xyloccensin-I were found to show activity equivalent to the parent active fraction in vitro model.

Murraya koenigii (L.) Spreng. ameliorates insulin resistance in dexamethasone‐treated mice by enhancing peripheral insulin sensitivity

BACKGROUND Murraya koenigii (L.) Spreng. is an important medicinal plant used traditionally as an antiemetic, antidiarrhoeal agent and blood purifier and as a medicine for a variety of ailments. This study investigated the effects of ethanolic extract of M. koenigii (MK) on diabetes-associated insulin resistance induced in mice by chronic low-dose injection of dexamethasone. RESULTS Mice treated with dexamethasone exhibited hyperglycaemia and impaired glucose tolerance. Treatment with MK reduced the extent of dexamethasone-induced hyperglycaemia and decreased insulin resistance as indicated by improved glucose tolerance and increased insulin-stimulated AKT phosphorylation in skeletal muscle tissue. Further evaluation in clonal skeletal muscle cell lines suggested that MK increased glucose uptake in L6 skeletal muscle cells by increasing cell surface GLUT4 density via an AKT-mediated pathway. CONCLUSION MK can ameliorate dexamethasone-induced hyperglycaemia and insulin resistance in part by increasing glucose disposal into skeletal muscle.